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Regulation of P-glycoprotein by miR-27a-3p at the Brain Endothelial Barrier

Hammad, Saba; Mabondzo, Aloïse; Hamoudi, Rifat; Harati, Rania; (2022) Regulation of P-glycoprotein by miR-27a-3p at the Brain Endothelial Barrier. Journal of Pharmaceutical Sciences , 111 (5) pp. 1470-1479. 10.1016/j.xphs.2021.10.021. Green open access

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Abstract

Multi-drug resistance P-glycoprotein (P-gp/MDR1) is one of the most clinically relevant ABC transporters, highly enriched at the blood-brain barrier (BBB) with a broad substrate spectrum including therapeutic drugs and metabolic waste products. Altered P-gp transport function has been implicated in multi-drug resistance and in the pathogenesis and progression of neurological diseases. Recent studies have shown that P-gp expression is modulated by micro-RNAs in peripheral organs. Particularly, miR-27a-3p has been shown to play a critical role in the regulation of P-gp in multi-drug resistant cancer cells. In brain disorders, altered levels of miR-27a-3p were reported in several diseases associated with alterations in P-gp expression at the BBB. However, effect of altered miR-27a-3p expression on P-gp expression at the BBB remains to be determined. In this study, we investigated the role of miR-27a-3p in the regulation of P-gp expression and activity at the brain endothelium. Levels of miR-27a-3p were modulated by mimic and inhibitor transfection in an in-vitro model of human brain endothelial hCMEC/D3 cells. Effect of miR-27a-3p modulation on P-gp expression and activity was examined and the underlying regulatory mechanisms explored. Our results showed that transfection of hCMEC/D3 cells with miR-27a-3p mimic induces expression and activity of P-gp while miR-27a-3p inhibition exerted opposite effects. Mechanistic studies revealed that miR-27a-3p regulates P-gp by mediating Glycogen Synthase Kinase 3 Beta (GSK3ß) inhibition and activating Wnt/ß-catenin signaling. These findings shed light on miR-27a-3p/GSK3ß/ß-catenin as a novel axis that could be exploited to modulate P-gp efflux activity at the brain endothelium and help improving CNS diseases treatment or brain protection.

Type: Article
Title: Regulation of P-glycoprotein by miR-27a-3p at the Brain Endothelial Barrier
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.xphs.2021.10.021
Publisher version: https://doi.org/10.1016/j.xphs.2021.10.021
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: miR-27a-3p, p-glycoprotein, GSK3ss, Wnt, ss-catenin, Brain endothelium, Blood-brain barrier
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10154641
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